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Largest exome studies to date establish critical new resources for biomedical community

Newswise — NEW YORK, NY The Icahn School of Medicine at Mount Sinai today announced the publication of two papers in the journal Nature that reveal new information about the genetic complexity underpinning schizophrenia. These collaborative studies represent the largest exome sequencing efforts to date to elucidate this mental illness, and together found that the disorder is likely caused by far more rare genetic mutations than previously suspected.

In the publications, Mount Sinai scientists and their collaborators at the Broad Institute, Sanger Centre, Cardiff University, University of North Carolina, and the Karolinska Institute report large-scale projects that sequenced the genes of 6,948 people in Bulgaria and Sweden, including patients diagnosed with schizophrenia, their parents and healthy controls. Both studies determined that a very large number of rare genetic mutations contribute to risk for the disease, rather than only a few ‘faulty’ genes. The clinical and genetic information gathered on more than 3,000 affected individuals has produced the world’s largest database on schizophrenia, a resource that will be invaluable to the biomedical community in continued efforts to elucidate factors that contribute to the disease.

“These new exome studies indicate that the genetic basis of schizophrenia is tremendously complex and will require further research to add RNA, protein, and other layers of data to the picture we are building,” said Eric Schadt, PhD, the Jean C. and James W. Crystal Professor of Genomics at the Icahn School of Medicine at Mount Sinai, and Director of the Icahn Institute for Genomics and Multiscale Biology, part of the Mount Sinai Health System. “Now that we have this critical information, we can embark on the kind of massive-scale network analysis that our scientists have successfully used to characterize other complex diseases and start to think about new ways to treat these patients.”

Schizophrenia is a chronic, often debilitating mental illness that affects 1 percent of the global population, including 2.4 million American adults. Symptoms include persistent auditory and visual hallucinations, delusions, and paranoia, among others. Patients today are treated with antipsychotic therapies that have seen little innovation in the last 20 years. Familial studies have consistently demonstrated a large role for inherited factors, arguing for continued genetic studies.

“The sheer volume of data generated in these projects is remarkable and suggests new ways of thinking about the role of rare mutations in schizophrenia,” said Shaun Purcell, PhD, lead author of the Swedish population study and head of the Center for Statistical Genomics at Mount Sinai. “Although the complexity of the genetics is sobering, these types of studies should provide a firm base from which we can chart a course toward the ultimate goal of subtyping patients and offering a more personalized treatment path than the one-size-fits-all approach currently used.”

Details of the two publications:

• “A polygenic burden of rare disruptive mutations in schizophrenia” by Shaun Purcell et al. This paper performed exome sequencing on 2,536 cases and 2,543 controls collected by the Karolinska Institute in Sweden. The authors report that many ultra-rare mutations across dozens of genes, particularly those related to proteins that influence brain circuitry, contribute to a person’s risk of schizophrenia. Authors of this paper include researchers at the Stanley Center for Psychiatric Research at the Broad Institute, the Icahn School of Medicine at Mount Sinai, Massachusetts General Hospital, Karolinska Institute, Wellcome Trust Sanger Institute, University of Edinburgh, Harvard Medical School, and University of North Carolina.• “De novo mutations in schizophrenia implicate synaptic networks” by Menachem Fromer et al. This paper reports the exome sequencing of 623 trios (parents and affected child) from Bulgaria and analysis of de novo mutations, finding some overlap between genes implicated in schizophrenia with ones already associated with autism and intellectual disability. De novo mutations fell in synaptic protein networks. Authors came from the Icahn School of Medicine at Mount Sinai, the Broad Institute, Cardiff University, Wellcome Trust Sanger Institute, University of Tartu, Medical University of Sofia, University of Helsinki, University of Edinburgh, Harvard Medical School, and Massachusetts General Hospital.

Funding for the studies was provided by the Friedman Brain Institute and the Icahn Institute for Genomics and Multiscale Biology at Mount Sinai, the National Institute of Mental Health, the National Human Genome Research Institute, the Sylvan Herman Foundation, a philanthropic gift from K. and E. Dauten, the Stanley Medical Research Institute, the Swedish Research Council, Medical Research Council, the European Community’s Seventh Framework Programme, Fidelity Foundations, The Wellcome Trust, and the European Commission.

About the Mount Sinai Health SystemThe Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care.

The System includes approximately 6,600 primary and specialty care physicians, 12-minority-owned free-standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report. For more information, visit www.mountsinai.org.